Central involvement of kinin B₁ and B₂ receptors in the febrile response induced by endotoxin in rats

Abstract

1. The effect of central injection of selective kinin B₁ and B₂ receptor antagonists on the febrile response induced by endotoxin (E. coli lipopolysaccharide, LPS) in rats was investigated.

2. Intracerebroventricular (i.c.v.) injection of a selective B₂ receptor antagonist (Hoe-140, 8 nmol) reduced the early (0–2 h), but increased the late phase (4–6 h) of the febrile response induced by intravenous (i.v.) injection of LPS (0.5 μg kg⁻¹).

3. Co-administration of Hoe-140 (8 nmol, i.c.v.) with LPS (0.5 μg kg⁻¹, i.v.), followed 2.5 h later by the i.c.v. injection of a selective B₁ receptor antagonist [des-Arg⁹-Leu⁸]-bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period.

4. Intravenous injection of Hoe-140 (1 mg kg⁻¹) significantly reduced the febrile response induced by LPS (0.5 μg kg⁻¹, i.p.).

5. Pretreatment (24 h) with LPS (0.5 μg kg⁻¹, i.v.) reduced the febrile response induced by BK or [Tyr⁸]-BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des-Arg⁹]-BK (5 nmol, i.c.v.). The response induced by [des-Arg⁹]-BK in LPS-pretreated rats was significantly inhibited by co-injection of [des-Arg⁹-Leu⁸]-BK (15 nmol, i.c.v.).

6. The results suggest that kinins are involved in the induction of LPS-induced fever and that central B₂ and B₁ receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B₂ receptors and induction and/or upregulation of B₁ receptors in LPS-pretreated animals may have a significant pathophysiologcal role in the induction and maintenance of fever. These observations may be specifically important in the case of chronic inflammatory conditions, because the BK metabolite [des-Arg⁹]-BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B₁ receptors that occurs in such states.

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